PROJECT SUMMARY Environmental exposures during gestation can alter early growth trajectories and increase the risk of developing chronic diseases including diabetes, hypertension, and obesity. Among the exposures of greatest concern is cadmium, a metal that is extensively used in the electronics industry. Cadmium is a high priority toxicant with adverse clinical effects reported in both adults and children. During pregnancy, cadmium accumulates in the placenta where it induces cellular stress, interferes with hormone production, and limits the transfer of nutrients from mother to child. This leads to smaller offspring size at birth in humans and animal models. Identifying cellular mechanisms that can modify cadmium?s toxicity in the placenta are key to preventing the adverse outcomes associated with fetal growth restriction due to cadmium, a chemical that will persist in our environment for the foreseeable future. One mechanism that reduces placental accumulation of environmental chemicals is active transport by efflux proteins. The breast cancer resistance protein (BCRP/ABCG2), an efflux transporter highly expressed on syncytiotrophoblasts, plays a critical role in restricting the placental accumulation of chemicals. The overarching hypothesis of this research is that BCRP is a critical mechanism limiting placental exposure to cadmium; when BCRP function is reduced, cadmium?s toxic effects on the placenta are enhanced, resulting in fetal growth restriction. This hypothesis will be tested in three specific aims using innovative and translational experimental approaches. The multidisciplinary research team includes a biochemical toxicologist, biomedical engineer, and an epidemiologist. To study the ability of BCRP to prevent cadmium-induced placental toxicity, a complement of culture models, including a novel ?Placenta-on-a-Chip? as well as term villous explants from healthy pregnancies will be used. To test the in vivo ability of BCRP to prevent cadmium-induced fetal growth restriction, transgenic pregnant mice will be treated with cadmium chloride and evaluated for placental toxicity and fetal growth restriction. The UPSIDE cohort of 310 healthy, pregnant women will be examined for prenatal exposure to metals, including cadmium, and transporter genomics/proteomics in relation to 3D placental morphology and infant growth outcomes. Ultimately, this line of research will inform the scientific community regarding the ability of placental transporters to protect the fetus from environmental chemical-induced developmental toxicities.